Pendant hydrophile bearing biodegradable compositions and related devices

ABSTRACT

A composition comprising at least one polymer having the structure A-B-A′, wherein A and A′ may be the same or different and each is a degradable polyester component and wherein B is the reaction product resulting from the reaction between a diol, having one or more pendant oligomeric or polymeric groups, and A and A′. Additionally, a bioresorbable patch comprising: (a) an adhesion barrier component comprising the composition in the form of a film; and (b) an adhesive component comprising (i) at least one synthetic adhesive polymer and/or (ii) at least one polysaccharide. Also, a method of wound healing, comprising administering the composition or apply the patch to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of copending application Serial Ser.No. 13/880,666, filing date Oct. 23, 2013. Application Ser. No.13/880,666 is the U.S. national phase of international application No.PCT/EP2011/068379, filed Oct. 20, 2011. Benefit under 35 U.S.C. §119(e)is claimed to U.S. Provisional Application No. 61/394,771, filed on Oct.20, 2010. Each of these applications is expressly incorporated byreference into the present application.

BACKGROUND OF THE INVENTION

The instant invention relates to a composition comprising at least onepolymer having the structure A-B-A′, wherein A and A′ may be the same ordifferent and each is a degradable polyester component and wherein B isthe reaction product resulting from the reaction between a diol, havingone or more pendant oligomeric or polymeric groups, and A and A′.

Additionally, the invention also relates to the development of abioresorbable patch comprising:

-   -   (a) an adhesion barrier component comprising a composition        according to the invention in the form of a film; and    -   (b) an adhesive component comprising:    -   (i) at least one synthetic adhesive polymer; and/or    -   (ii) at least one polysaccharide.

The present invention provides a method of wound healing, comprisingadministering the composition or patch

The instant invention further relates to bioresorbable polymers andparticularly ones containing pendant and/or terminal oligomeric orpolymeric end groups on a polymer backbone and biomedical devices madethereof. The backbone polymer can essentially be composed ofbioresorbable polymers such as poly (hydroxy acids) and theirderivatives that are linked, coupled, or chain extended to formfunctional polymers. Applications of these compositions include use as abarrier film for preventing post surgical adhesions, as a porousscaffold material for wound healing, and use as a medium to incorporatespecific pharmaceutical compounds or biologically active components tosupport targeted therapeutic treatment.

Poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) are uniquebiocompatible polymers used in a variety of biomedical implant devices,such as controlled and targeted drug delivery systems, adhesionbarriers, and tissue engineering applications. In an interestingcommentary on a published paper by Sheth and Leckband (Sheth, S. R. andLeckband, D. Measurements of attractive forces between proteins andend-grafted poly(ethylene glycol) chains, Proc. Natl. Acad. Sci., 94,8399-8404 (1997)) by Israelachvili (Israelachvili, J., The differentfaces of poly (ethylene glycol), Proc. Natl. Acad. Sci., 94, 8378-8379(1997)), he discusses the characteristics of PEO, especially withregards to miscibility in aqueous media, ability to repel proteins andbeing repelled by proteins while enabling the dissolution and controlledrelease of drugs.

U.S. Pat. No. 6,677,362 discloses the use of solid dispersions ofwater-insoluble drugs in hydrophilic polymers, such aspolyvinylpyrrolidone (PVP), or high molecular weight PEO, from aqueoussolutions for improved bioavailability. U.S. Pat. No. 4,188,373discloses the use of PEO-PPO-PEO block copolymers as sol-gel vehicles inpharmaceutical compositions that are soluble in water at roomtemperature, and has a gel transition temperature in the bodytemperature range (25-40° C.). The primary constraint of drugincorporation by this method arises from the severe differences in thewater solubility of the polymer and the drug resulting in poordrug-loading capacity and efficiency.

U.S. Pat. No. 4,911,926 discusses the use of aqueous and non-aqueouscompositions comprising polyoxyalkylene block copolymers in reducingpost surgical adhesion formation. However, PEO and PPO are notbiodegradable, and hence their use is restricted to low molecularweights so that they can be resorbed easily by the body. This seriouslylimits the use of PEO and PEO-PPO-PEO block copolymers by themselves asan adhesion barrier because low molecular weight PEO and PEO-PPO-PEO areabsorbed at a much faster rate than the wound healing process. Also, lowmolecular weight PEO and PEO-PPO-PEO are soft materials and theirapplications are limited to biomedical areas where strength is not arequirement.

Aliphatic polyesters as medical implant devices have been studiedextensively. Kulkarni, et al., discuss the development of syntheticbioresorbable polyesters produced by ring opening polymerization ofL-lactide for implant studies (Kulkarni, et al., Biodegradable poly(lactic acid) polymers, J. Biomed. Mater. Res., Vol 5, 169-181, (1971)).These aliphatic polyesters are characterized by high strength (that canbe processed into biomedical articles), low elongation, biocompatibilityand degradation over a long period of time.

In an attempt to improve the biodegradability while not impacting on thetensile properties, U.S. Pat. No. 3,636,956 discloses the development ofhigh strength aliphatic polyesters, viz. copolymers of L-lactide andglycolide that are fast degrading. Similarly, U.S. Pat. No. 4,438,253discloses multiblock copolymers produced by transesterification of PEOand poly (glycolic acid) for use in surgical articles with goodflexibility and faster biodegradability.

U.S. Pat. No. 4,826,945 discloses the synthesis of ABA type blockcopolymer composed of polyethylene oxide (PEO) and α-hydroxy carboxylicacid using a one-step process. The process essentially involves the ringopening polymerization of L-lactide, glycolide, caprolactone or othersimilar monomers using PEO of desired molecular weight and in thepresence of catalyst at high temperatures. The ABA block copolymergenerated is low molecular weight with terminal hydroxyl groups that ischain extended to very high molecular weights by reacting with adiisocyanate to yield polyetheresterurethane. Unlike polyesters that arerigid and having low extensibility, these polyetheresterurethanes areelastomeric, i.e. flexible and having high extension.

U.S. Pat. No. 4,826,945 discloses the use of Sb₂O₃ as the esterificationcatalyst for the ring opening polymerization, while the use of tinoctoate as an efficient ring opening polymerization (esterification)catalyst has been reported in U.S. Pat. No. 3,839,297. U.S. Pat. No.5,711,958 describes the sequential use of stannous octoate as a catalystfor the esterification reaction and chain extension reaction with adiisocyanate. The advantage of using stannous octoate as theesterification catalyst lies in its extended use as a catalyst in thesubsequent polyurethane reaction.

U.S. Pat. Nos. 5,711,958; 6,136,333; 6,211,249, 6,696,499; 7,202,281further discuss the use of AB and ABA type polymers as adhesion barriersfilms in their hydrated form. However, significant amounts of PEO arerequired in the polymer to enable it to successfully function as anadhesion barrier. Even so, the efficacy of the entire polymeric material(in the form of films) to inhibit post surgical adhesions is limited andas much as one-third of the test population treated with these polymersreportedly developed severe adhesions

The use of A-B, ABA and BAB type block copolymers, wherein, A=PEO orPEO-PPO and B=polyesters or poly(ortho esters) as bioresorbable drugdelivery systems has been reportedly discussed in patent disclosures andjournal literature. U.S. Pat. No. 4,526,938 discloses the use of ABAtype of polyesters for use in tunable sustained release of drugs. Bymanipulating the amount of hydrophobic polyester component in thecopolymer, it was possible to adjust the length of time for sustaineddrug release. U.S. Pat. No. 7,649,023 discloses the use of low molecularweight PEO in the development of oligomeric multiblock polyesters asfree flowing liquid or water-reconstitutable drug carriers.

Whereas the above literature teaches the use of block copolymerscontaining poly(oxyalkylene) units for making different biomedicaldevices, there are other arrangements of the hydrophilic PEO unitswithin the polymer structure that are recently being utilized fordifferent applications. WO 2009/073192 A2 discloses the use of pendantside chain crystallizable (SCC) polymers as carriers for drug releaseapplications. Polymeric release compositions with systems and methodsfor delivering release materials, for e.g. drugs and other bioactivematerials have been described. In addition, use of the compositions astissue scaffolds, ocular inserts, for delivery of nucleotides, and indrug eluting stent applications have been described.

A recent review article, (Neil Ayres (Ayres, N., Polymer brushes:Applications in biomaterials and nanotechnology, Polymer Chemistry, Vol1, 2010, 769-777)) examines the uses of surface confined macromoleculesor polymer brushes for surface and interface applications in areas ofbiomaterials and nanotechnology. As described earlier, pegylatedsurfaces (and other similar hydrophilic poly(oxyalkylene) amphiphiles)are “first approach” strategy for developing biocompatible devices.Leckband et al. (Leckband et al., Grafted (polyethylene oxide) brushesas non-fouling surface coatings, J. Biomater. Sci. Polymer Edn., 10(10),1999, 1125-1147) describe the theoretical and quantitative aspects ofgrafted PEO brushes in preventing protein adsorption. They determinedthat controlling the graft density and molecular weight of PEO can beutilized to control, prevent or retard protein adsorption. Furthermore,the polymer segments of the grafted PEO brushes under hydratedconditions are predominantly amorphous.

Recently numerous accounts of using pendant side chain containingamphiphilic polyurethanes for improved control and stabilization ofcolloidal dispersions in aqueous media have been reported fornon-medical applications. WO 2009013316 describes the use of pendantpolyoxyalkylene based 1, 3 diols (Tegomer D3403, Tegomer D 3123 andTegomer D3409) in the preparation of a water-dispersible polyurethaneusing a polyisocyanate crosslinker. WO 2007023145 discloses the use ofpendant MPEG based 1, 3 diol for the synthesis of polyurethanedispersant coatings with good pigment dispersibility and stability.

The use of PVP as an adhesive for general purposes is known. Goodadhesion to plastic surfaces, such as polyethylene terephthalate (PET)is disclosed in commercially available product literature, such as byBASF. U.S. Pat. No. 5,143,071 discloses the development of highlyconducting non-stringy PVP and PEO based adhesive gels for applicationto skin to provide electrical contact for medical devices.

U.S. Pat. No. 7,727,547 describes a tissue adhesive formulation whichconsists of polymerizable and/or cross-linkable material in particulateform, the said material being in admixture with particulate materialcomprising tissue-reacting functional groups. The patent also describesapplication of such formulation to one side of a core of a naturallyoccurring or synthetic polymeric material. The adhesive polymerdescribed in the patent comprises of reaction product ofpoly(N-vinyl-2-pyrrolidone-co-acrylic acid) co-polymer and a reactantcomprising a tissue-reacting functional group.

U.S. Pat. No. 5,508,036 claims a device for preventing adhesions whichcomprises a composite of a first layer and a second layer, each of whichcomprises a biodegradable polymer of different pore size and optionallywith an adherence layer to support the adhesion barrier and to enableattachment of the device without suturing.

SUMMARY OF THE INVENTION

The object of the invention is the development of compositionscomprising biodegradable amphiphilic polyesters have the advantage ofretaining better mechanical integrity prior to onset of degradation incontrast to the ABA triblock biodegradable polymers according to theprior art described above.

This is achieved by a composition comprising at least one polymer havingthe structure A-B-A′, wherein A and A′ may be the same or different andeach is a degradable polyester component and wherein B is the reactionproduct resulting from the reaction between a diol, having one or morependant oligomeric or polymeric groups, and A and A′.

A further advantage of the compositions according to the invention isthat the surface of a device manufactured from the compositions ishydrophilic or hydrophobic enriched and presents superior functionalproperties compared to the ABA triblock copolymers of the prior art. Forexample the polymers according to this invention can form a barrier forpreventing post surgical adhesions.

Another advantage of the compositions according to the invention is thatthe amphiphilic property of the polymeric material in the compositionsof the invention enables the dispersion and uniform distribution ofbioactive agents in the polymer matrix. In this way the bioactive agentscan released into the immediate tissue environment or intended site at adesired dose rate as the polymer degrades over the period of time.

Another advantage of the compositions according to the invention is thatthe ratio of the alkylene oxide units to the degradable ester linkagesin the polymer composition allows tunability of the mechanicalproperties desired for a specific application.

Another advantage of the compositions of the present invention is thatthe compositions can be formed into a film which can be used in abioresorbable adhesive patch containing a PVP based adhesive coated onthe film of the composition according to the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an example of an adhesive patch according to the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The instant invention relates to bioresorbable polymers, including onescontaining pendant and/or terminal oligomeric or polymeric end groups ona polymer backbone and biomedical devices made therefrom. The backbonepolymer is essentially composed of bioresorbable polymers such as poly(hydroxy acids) and their derivatives that are linked, coupled, or chainextended to form functional polymers. This invention also disclosesapplication of the aforementioned biodegradable compositions in thebiomedical field.

The invention relates more specific to a composition comprising at leastone polymer having the structure A-B-A′, wherein A and A′ may be thesame or different and each is a degradable polyester component andwherein B is the reaction product resulting from the reaction between adiol, having one or more pendant oligomeric or polymeric groups, and Aand A′.

Preferably, A and A′ each comprise a poly hydroxyl carboxylic acid. A orA′ in the present invention preferably comprise poly (hydroxylcarboxylic acids), because these polymers will degrade and producemonomeric units which may be readily metabolized by the patient. The Aor A′ unit of the polymers may therefore also be referred to as “thedegradable polyester”, and generally may optionally include aliphaticpolycarbonate segments. Aliphatic polycarbonate segments may includepoly(alkylene carbonates) such as poly(trimethylene carbonate) that isknown by one skilled in the art to be used as a component in the fieldof bioresorbable polymers.

The terms “poly(hydroxy carboxylic acid)” or “poly(α-hydroxy carboxylicacid)” are used to describe the polyester A and A′ structures of A-B-A′structure used in polymeric compositions according to the presentinvention where A or A′ is a polymeric polyester unit derived from analiphatic hydroxy carboxylic acid or a related ester or dimeric ester. Aand A′ preferably are derived from an aliphatic α-hydroxy carboxylicacid or related ester, including a cyclic dimeric ester. Examples ofmonomers that can be used to form the polyesters A and A′ are lacticacid, lactide, glycolic acid, glycolide, or a related aliphatichydroxycarboxylic acid or ester (lactone) such as, for example,ε-caprolactone, δ-glutarolactone, δ-valerolactone, γ-butyrolactone,β-butyrolactone, β-propriolactone, 1,5-dioxepan-2-one, pivalactone,1,4-dioxane-2-one, and mixtures, thereof. The α-hydroxy acids and theircorresponding cylic dimeric esters, especially lactide and glycolide canbe used in the present invention

Further the polymer comprises B, which is the reaction product resultingfrom the reaction between a diol, having one or more pendant oligomericor polymeric groups, and A and A′. B may “result from” a diol or is thereaction product of a diol, containing a pendant oligomeric or polymericgroup. As known to one of skill in the art, a pendant group or a sidegroup is generally a cluster of molecules arranged in linear or branchedconformations and attached to the backbone polymer chain.

For the purpose of this invention, the pendant moieties and theirderivatives may be either hydrophobic or hydrophilic, and may generallyinclude polyalkylene oxides, such as poly(ethylene glycol),poly(propylene glycol), PEO, PPO, PEO-PPO copolymers, mixtures thereofand their monoalkyl derivatives.

When B is hydrophobic, the desired pendant groups of the presentinvention include substantially linear alkyl and/or alkenyl hydrocarbonscontaining preferably alkyl and/or alkenyl groups comprising 3 to 30carbon atoms (C3-C30 alkyl and/or alkenyl groups), more preferablybetween C5 to C25 and most preferably between C8 to C18. Examples ofalkyl groups are, in particular, propyl, isopropyl, n-butyl, 2-butyl,sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl,1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl,2-ethylbutyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-heptyl, 3-heptyl,2-ethylpentyl, 1-propylbutyl. n-octyl, 2-ethylhexyl, 2-propylheptyl,nonyl, decyl and so on. Suitable longer-chain C8-C30-alkyl orC8-C30-alkenyl groups are straight-chain and branched alkyl or alkenylgroups; for example octyl(ene), nonyl(ene), decyl(ene), undecyl(ene),dodecyl(ene), tridecyl(ene), tetradecyl(ene), pentadecyl(ene),hexadecyl(ene), heptadecyl(ene), octadecyl(ene), nonadecyl(ene).

For the purposes of the present invention, when B is hydrophilic, thependant groups of choice are generally derived pendant oligomeric orpolymeric oxyalkylene moiety, such as poly(ethylene glycol) (PEG),poly(propylene glycol (PPG), polyethylene oxide (PEO) and/orpolypropylene oxided (PPO) and/or polyethylene oxide-polypropylene oxide(PEO-PPO) comprising groups. mixtures thereof and their monoalkylderivatives.

The pendant group of B in the polymer A-B-A′ preferably comprises ahydrophilic group.

More preferably, the pendant group in B comprises a polyvinylpyrrolidone(PVP) or poly(dimethylacrylamide) (PDMA) group. is a

The terms “poly(ethlyene glycol)”, “poly(oxyethylene)” and “polyethyleneoxide” are used interchangeably in reference to the present invention.

The term “resulting from” or “derived from” is intended to mean “madefrom” through single or multiple chemical reaction steps and the term“derivative” is intended to mean different examples or analogues of ageneral chemical composition.

In the present invention, the A-B-A′ structure is a unit which isgenerally derived from poly(hydroxy acid) polymers in the A block andpoly(oxyalkylene) polymers in the B unit. The A block and the A′ blockof the A-B-A′ structure of the present polymers are biodegradable andranges in size from one monomeric unit up to about 200 or more monomericunits, with a preferred size ranging from about 4 to about 50 units,more preferably about 6 to about 30 units, even more preferably about 8to 16 units. The A block preferably is derived from an alpha-hydroxyacid or a related ester or lactone which produces monomer units ofalpha-hydroxy acid within the polymeric chain as will be described ingreater detail below. More preferably the A block is derived from unitsof glycolic acid, lactic acid (preferably L, or D, L mixtures to promotebioabsorbability) or mixtures thereof, in the form of glycolide orlactide reactants (dimeric α-hydroxy acids as explained in greaterdetail herein below). The B unit preferably comprises a diol precursorcontaining pendant poly(ethylene oxide) or poly(ethyleneoxide-co-propylene oxide) copolymers. The B unit may vary in size fromabout 200 Da (dalton units) up to about 200,000 Da or higher, with apreferred range of about 1,000 Da up to about 20,000 Da. Mostpreferably, the B unit has a pendant poly(ethylene oxide) ranging insize from about 3,000 to about 10,000 Da. It is unexpectedly that thepoly(ethyleneoxide) B unit provides the greatest inhibition or reductionin adhesion in the present invention.

The present bioresorbable polymers can be chain extended and/orend-capped. For instance, the present polymers are preferably end-cappedwith hydroxyl groups and are chain-extended using difunctional chainextenders such as diisocyanates, dicarboxylates, diesters or diacylhalide groups in order to chain extend the A-B-A′ structure into highmolecular weight polymer chains. Examples of aliphatic diisocyanatesinclude 1,2-diisocyanatoethane, 1,4-diisocyanatobutane,1,5-diisocyanatopentane, 1,6-hexamethylene diisocyanate, lysine esterdiisocyanate, Tetramethylxylylenediisocyanate (TMXDI), isophoronediisocyanate, hydrogenated methylenediphenyldiisocyanate (HMDI) andother diisocyanates known to those skilled in the art or any combinationof these. Examples of the an aromatic diisocyanates include toluenediisocyanate, methylenediphenyldiisocyanate (MDI), and otherdiisocyanates known to those skilled in the art or any combination ofthese. The chain-extenders may be multifunctional chain extenderscontaining isocyanate reactive groups, such as for e.g. hydroxyl,carboxylic acid, thiol, oxiranes, or amines. Other specific examplesinclude trimethylol propane, pegylated amines, alcohols, thiols, aminoacids, and oligomers such as trilysine.

Preferably, one or more polymers with the structure A-B-A′, according tothe invention are chain extended with a diisocyanate compound to form apolyesterurethane.

Alternatively, the polymers may be end-capped with groups such ascarboxylic acid moieties or ester groups (which may be reacted directlyas ester groups, activated as “active” ester groups or converted toactive acyl groups such as acyl halides) or isocyanate groups and thenreacted with difunctional chain extenders such as diols, diamines, orhydroxylamines among others, to produce chain extended polymers havinghigh molecular weight. The isocyanates used in the end-caps aregenerally monofunctional, and include alkyl isocyanates such as octylisocyanate and decyl isocyanate, or alkoxy isocyanates such asmonofunctional PEG isocyanate. The polymers of the present invention mayalternatively have a non-reactive end group, which is non-reactive withother chemicals in the polymer or composition.

Preferably, the polymers according to the present invention areend-capped with a monofunctional isocyanate compound.

The term “chain-extended” is used to describe polymers according to thepresent invention wherein the basic triblock is reacted with adifunctional chain-extender to increase the molecular weight of thepresent polymers. The present polymers are chain-extended to providesufficiently high molecular weight polymer chains to enhance thestrength and integrity of the final polymer compositions as well asaffecting the rate of degradation. It is noted that chain extension ofthe polymers provides adequate strength and integrity of the final filmsand other structures, yet allows a degree of mobility of the individualpolyoxyalkylene present in the B units within the A-B-A′ structure inorder to maximize the adhesion inhibiting characteristics of the films.The chain extenders which are used are difunctional compounds whichreact with the end-cap group of the A-B-A′ structures to produce thechain extended A-B-A′ structures according to the present invention. Inthe present invention, the amount of chain extender which is includedwithin the polymers according to the present invention may vary. Thus,the molar ratio of chain extender to A-B-A′ structure in the presentpolymers varies from about 0.5 to about 2.0 (about 1:2 to about 2:1,based upon the number of moles of difunctional chain extender and thenumber of moles of A-B-A′ polymer), more preferably about 0.8 to about1.2 and most preferably about 1.0. It is noted that in synthesizing thepresent chain-extended polymers, the mount of chain extender which isreacted with difunctional triblock to produce polymer, is generallyslightly higher than the amount which is expected to be included in thefinal synthesized polymers. Chain extenders which are used in thepresent invention, preferably contain no more than about 1% by weight ofa crosslinking compound (such term signifying a compound containing atleast 3 functional groups which can react with the end-cap group of thetriblock and which generally appear in a chain extender sample as a sideproduct of the synthesis or production of the chain extender), morepreferably, less than about 0.5% by weight of a trifunctional compoundand even more preferably less than 0.1% by weight. It is most preferableto employ a difunctional chain extender which contains as littletrifunctional (or higher functionality) compound as is practical. Also,the occurrence of side reactions which would lead to crosslinking of thepolymers is negligible, due to both compositional as well asexperimental parameters of the synthesis of the polymers of the presentinvention.

The present polymers may contain self assembling groups. Self assemblinggroups can be one or more chemical groups, polymers or oligomers, suchas aliphatic alkyl oligomers. Self assembling end groups are discussedin published U.S. Application 2009/0258048 A1, the entire contents ofwhich are hereby incorporated by reference. Self assembly of the presentpolymers may be enabled by intermolecular and/or intramolecularnon-covalent binding forces.

Bioresorbable and biodegradable refer to the characteristic whereby apolymer will degrade hydrolytically, oxidatively or enzymatically in thebody. The polymers according to the present invention readily hydrolyzein vivo and breakdown readily into monomeric units of hydroxy acids. Inthe case of the PEG chains in the B unit, although these are notbiodegradable, they are readily excreted by the patient upon degradationof the A block. The degradation of the present polymers primarily occursthrough the hydrolysis of the ester bond in the A block under bodyphysiological pH conditions. The hydrolysis reaction is generallydependent upon pH. The rate constant for hydrolysis tends to be muchhigher at high pH (greater than 9.0) and low pH (less than 3.0) than atneutral pH (6.0 to 8.0). The rate constant for hydrolysis tends to behigher under basic conditions than under acidic conditions.

The degradation properties of the present polymers are “tunable”. Therate of hydrolytic degradation can be slowed substantially by using thehydrophobic pendant groups or by using esters derived fromε-caprolactone, δ-glutarolactone, δ-valerolactone, γ-butyrolactone,β-butyrolactone, β-propriolactone, 1,5-dioxepan-2-one, pivalactone,1,4-dioxane-2-one and mixtures thereof. Likewise, the rate of hydrolysiscan be accelerated by using hydrophilic pendant groups, such as PEO,PPO, PEO-PPO copolymers, PVP, PDMA, phosphoryl choline or by usingesters derived from L-lactide, D,L-lactide, glycolide and mixturesthereof.

The presence of hydrophilic poly(alkylene oxide) units as pendant groupswith or without terminal hydrophilic moieties in the relativelyhydrophobic polymeric back bone is capable of imparting amphiphilicproperties that are suitable in biomedical device applications. Inaddition, the polymers of this invention have the advantage of retainingbetter mechanical integrity prior to onset of degradation in contrast tothe ABA triblock biodegradable polymers known in the art. Furthermoreenrichment of the surface of a device manufactured from polymers of thisinvention can present superior functional properties compared to the ABAtriblock copolymers of the prior art. For example the polymers accordingto this invention can form a barrier for preventing post surgicaladhesions. The amphiphilic property of the polymeric material enablesthe dispersion and uniform distribution of active agents in the polymermatrix. The bioactive agent(s) loaded polymer matrix can be convertedinto a biomedical device, such as an adhesion barrier or a tissuescaffold and optionally implanted at the wound site. The bioactiveagents are released into the immediate tissue environment or intendedsite at a desired dose rate as the polymer degrades over the period oftime.

The ratio of the alkylene oxide units to the degradable ester linkagesin the polymer composition allows tunability of the mechanicalproperties desired for a specific application.

The term “EO/LA ratio” is used to describe the relative amount ofpoly(ethylene oxide) and/or poly(ethylene oxide)-co-poly(propyleneoxide) with respect to hydroxy carboxylic acid (preferably, α-hydroxycarboxylic acid, most preferably, lactic acid) which is used in presentpolymers and chain-extended polymers according to the present invention.This term refers to the length (number of monomeric ethylene oxideunits) of the B unit [preferably, poly(ethylene oxide)] divided by thetotal number of α-hydroxy acid units in both A blocks (preferably,lactic acid) of the polymer as described hereinabove. When the ratiomeasures the ratio of ethylene oxide: L-lactide, the ratio may be termed“EO/LLA”. Polymers comprised of A-B-A′ structure described above whichare chain extended pursuant to the present invention are also describedin terms of an EO/LLA ratio. Polymers according to the present inventioncan have EO/LA ratios ranging from about 0.05 to about 100, orpreferably about 0.1 to about 20, or more preferably about 0.25 to about6.

The inherent water absorbing capacity of poly(alkyleneoxides) such aspoly(ethylene oxide) present in the compositions of this invention andselection of the biodegradable hydroxy acid groups in the polymers ofthis invention facilitate tunability of the degradation behavior for aspecific targeted application. Frequently, the “water absorbingcapacity” is affected by the hydrophilicity of a chain extender or anend group. Specifically “water absorbing end groups” may include PEO,PPO, PEO-PPO copolymers, PVP, PDMA, phosphoryl choline and other naturaland synthetic polymers known to those skilled in the art. “Non-waterabsorbing end groups” may include alkyl, silicon (or silicones), andfluorinated oligomers.

Furthermore, the presence of poly (ethylene oxide) segments in thepolymers of this invention is important to support adhesion barrierproperties in the hydrated form. See for example, U.S. Pat. Nos.5,711,958; 6,136,333; 6,211,249; 6,696,499; and 7,202,281 which areincorporated by reference in their entirety. The term “adhesion” is usedto describe abnormal attachments between tissues or organs or betweentissues and implants (prosthetic devices) which form after aninflammatory stimulus, most commonly surgery, and in most instancesproduce considerable pain and discomfort. When adhesions affect normaltissue function, they are considered a complication of surgery. Thesetissue linkages often occur between two surfaces of tissue during theinitial phases of post-operative repair or part of the healing process.Adhesions are fibrous structures that connect tissues or organs whichare not normally joined. Common post-operative adhesions to which thepresent invention is directed include, for example, intraperitoneal orintraabdominal adhesions and pelvic adhesions. Adhesions can occur afterall types of surgery including, for example, musculoskeletal surgery,abdominal surgery, gynecological surgery, ophthalmic, orthopedic,central nervous system, cardiovascular and intrauterine repair.Adhesions may produce bowel obstruction or intestinal loops followingabdominal surgery, infertility following gynecological surgery as aresult of adhesions forming between pelvic structures, restricted limbmotion (tendon adhesions) following musculoskeletal surgery,cardiovascular complications including impairing the normal movement ofthe heart following cardiac surgery, an increase in intracranialbleeding, infection and cerebrospinal fluid leakage and pain followingmany surgeries, especially including spinal surgery which produces lowback pain, leg pain and sphincter disturbance.

By “adhesion barrier properties” or “adhesion barrier functionality” itis meant the ability to prevent adhesions following surgical procedures,such as in the extra vascular space. The adhesion barrier properties canbe modified by selection of the molecular weight and by adjustingspatial density of the poly(ethylene oxide) segments in the pendant andthe terminal end group. For instance, if a polymer is chain extended,which adds MW and spreads out the spatial distance between poly(ethyleneoxide) segments between the pendant and terminal end groups, the polymerhas a superior barrier to adhesion. The present polymers of the A-B-A′form represents adhesion barrier polymers due to the presence of theseadhesion barrier properties.

Additionally, the composition may include bulk or surface propertymodifying additives. The bulk property is modified by incorporatingsuitable plasticizers, such as water, glycerol, sorbitol, PEO, PPO,PEO/PPO polymers, phthalate-based esters and other plasticizing estersknown to those skilled in the art. The surface properties of acomposition can be altered by providing “surface active compounds.”Surface active compounds and surface modifying additives are disclosedin published U.S. Application 2009/0258048 A1 the entire contents ofwhich are hereby incorporated by reference.

The term “homogeneous” is used to describe preferred polymers accordingto the present invention. The term homogeneous is associated with theinclusion in the final polymer compositions of a population of A-B-A′structures which are generally of the same size and preferably have apolydispersity of between about 1.0 and 4.0, more preferably about 1.1to about 2.0 and even more preferably about 1.1 to about 1.6.Homogeneous A-B-A structures are associated with reproducible mechanicaland physical characteristics and favorably consistent biodegradability.

The term “structure” is used to describe polymers according to thepresent invention by their molecular structure but also to describe astructure which has form, size and dimensions which are establishedoutside the body and will not significantly change upon being placedinside the body of the patient to be treated. The term structureembraces not only flat surfaced structures (i.e., films) in thetraditional manner, but also cylinders, tubes and other threedimensional structures which are not substantially changed by theanatomy of the patient into which the structure has been placed. Suchstructures may include porous constructs wherein the pore structure inthe polymer matrix has well-defined size; geometry; and distribution.Besides, the aforementioned characteristics, the pores may beinterconnected and the pore cells (each individual pore) may have anopen cell structure. These controls on the pore structures facilitatecell proliferation into the polymer matrix followed by soft-tissuegrowth and ultimately organ repair. Porous constructs are achieved usinga variety of techniques described in literature.

The term “gels” is used to describe dispersions or suspensions ofpolymer which have been formed by dissolving, suspending or dispersingpolymer in an aqueous solution for delivery to a site in or on thepatient's body in order to prevent adhesions. Gels of the presentinvention typically contain polymer in a sterile aqueous solution (suchsolution comprising saline solution, sterile water or a water/ethanolmixture) at a viscosity ranging from about 100 to about 100,000, orabout 500 centipoises units up to about 20,000 centipoises units ormore. The gels can be delivered in a sterile, isotonic saline solutionat a viscosity ranging from about 2000 centipoises units up to about20,000 centipoises units depending upon the application. In certainaspects according to the present invention, liquid polymericcompositions comprising non-water soluble polymers may also be used.

Gels according to the present invention may be used in numerousapplications to reduce or prevent adhesions, and can be employed toreduce or prevent adhesions following general surgical procedures andrelated surgeries which are minimally invasive. Gels may utilize anon-water soluble A-B-A′ structure, which is then chain-extended withwater-soluble or hydrophilic chain extenders in order to render theoverall polymeric composition water dispersible or water soluble.Certain phases within the gel polymer compositions will beadvantageously non-water soluble in order to promote the structuralintegrity and reduce the overall rate of biodegradability of the gelformulations in the body.

The term “viscous solution or suspension” is used to describe solutionsor suspensions of polymers according to the present invention whereinthe solution has a viscosity which is greater than about 1 centipoisesunit and is less than about 20,000 centipoises units, alternativelyabout 10 centipoises units to about 5,000 centipoises units, andalternatively about 100 centipoises units and above within this range.Viscous solutions or suspensions of polymers according to the presentinvention at viscosities approaching the high end of the range ofviscosities may be indistinguishable from gels at the low end of aviscosity range. The present invention also contemplates liquidpolymeric compositions having appropriate viscosity and flowcharacteristics and their use to reduce and/or prevent adhesions.

The term “foam” is used to describe open or closed cell porous solidforms wherein the pores within the solids are either fully or partiallyinterconnected.

The present A-B-A′ polymer structure can be used to form a “reactiveprepolymer”. A reactive prepolymer is a polymer that has not beencompletely reacted before being introduced or administered in anapplication, for example, to a patient to be treated.

Preferably, one or more polymers according to the present invention arereacted with an excess of diisocyanate to form a reactivepolyesterurethane prepolymer.

More preferably, the prepolymer is reacted with water or amultifunctional chain extender group selected from the group consistingof an amino, hydroxyl, or thiol compound to generate apolyesterurethaneurea, polyesterurethane, andpolyesterurethanethiourethane polymer.

The reactive prepolymer may polymerized in situ (i.e., at the site ofadministration) with a second component or may be polymerized as aresult of reaction between the prepolymer and the tissue surface. Incontrast, prepolymerized polymers of the present invention are utilizedto create both preformed structures, e.g., compositions havingthree-dimensional structure such as films, cylinders, spheres, rods,blocks, tubes, beads, foam or rings, etc. and related structures, andnon-preformed compositions such as sprays, gels, liquid polymers,pastes, viscous solutions and dispersions, among others.

General examples of bioresorbable polyesters, polyesterurethanes, andpolyesterurethane ureas are depicted in Formula 1a-e.

wherein X is O, S, or —CH₂—,

Y is C or N,

R₁ is H, an alkyl group containing 1-24 carbon atoms, a group containingan aromatic substituent, or a group containing multiple alkylene oxideunits of up to 500 units,

R₂ is alkyl group containing 1-12 carbon atoms,

R₃ is H, an alkyl group containing 1-24 carbon atoms, or an alkoxy groupcontaining multiple alkylene oxide units of up to 500 units,

n is 1-12,

a is 2-500, and

b is 1-100.

wherein X is O, S, or —CH₂—,

Y is C or N,

R₁ is H, an alkyl group containing 1-24 carbon atoms, a group containingan aromatic substituent or a group containing multiple alkylene oxideunits of up to 500 units,

R₂ is alkyl group containing 1-12 carbon atoms,

R₃ is H, an alkyl group containing 1-24 carbon atoms, or an alkoxy groupcontaining multiple alkylene oxide units of up to 500 units,

R₄ is a diisocyanate reaction fragment,

n is 1-12,

a is 2-500,

b is 1-100, and

c is 1-200.

wherein X is O, S, or —CH₂—,

Y is C or N,

R₁ is H, an alkyl group containing 1-24 carbon atoms, a group containingan aromatic substituent, or a group containing multiple alkylene oxideunits of up to 500 units,

R₂ is alkyl group containing 1-12 carbon atoms or a silicone containingfragment,

R₃ is H, an alkyl group containing 1-24 carbon atoms, or an alkoxy groupcontaining multiple alkylene oxide units of up to 500 units,

R₄ is a diisocyanate reaction fragment,

n is 1-12,

a is 2-500,

b is 1-100,

c is 1-200, and

d is 4-300.

wherein X is O, S, or —CH₂—,

Y is C or N,

Z is O, S, NH, or an N-alkyl group,

R₁ is H, an alkyl group containing 1-24 carbon atoms, a group containingan aromatic substituent, or a group containing multiple alkylene oxideunits of up to 500 units,

R₂ is alkyl group containing 1-12 carbon atoms,

R₃ is H, an alkyl group containing 1-24 carbon atoms, or an alkoxy groupcontaining multiple alkylene oxide units of up to 500 units,

R₄ is a diisocyanate reaction fragment,

R5 is an alkyl, silicone, alicyclic, heterocyclic, or an aromatic group,

n is 1-12,

a is 2-500,

b is 1-100,

c is 1-20, and

d is 4-300.

wherein X is O, S, or —CH₂—,

Y is C or N,

R₁ is H or an alkyl group containing 1-24 carbon atoms, a groupcontaining an aromatic substituent, or a group containing multiplealkylene oxide units of up to 500 units,

R₂ is alkyl group containing 1-12 carbon atoms or a silicone containingfragment,

R₃ is H, an alkyl group containing 1-24 carbon atoms, or an alkoxy groupcontaining multiple alkylene oxide units of up to 500 units.

a is 2-500,

b is 1-100, and

d is 4-300.

When R₁ is an aromatic substituent it is preferably a phenyl group or aderivative thereof.

The alkylene oxide units are preferably poly(ethylene oxide) units.

Specific examples of bioresorbable polyesters, polyesterurethanes, andpolyesterurethane ureas are depicted in Formula 2a-c.

wherein a is 23 units, and

b is 40 units.

wherein a is 23 units,

b is 40 units, and

c is 10 units.

wherein R₄ is a diisocyanate reaction fragment,

a is 23 units,

b is 40 units,

c is 10 units, and

d is 114 units.

Use of the Polymers in Biomedical Applications

The present bioresorbable polymers can be formed into gels, films, andother structures including rods, cylinders, sponges, foams, dispersions,viscous solutions, liquid polymers, sprays or gels. Such structures canbe implanted, administered topically, or administered by other meanssuch as injection. Applications of the present polymers includeimplantable medical devices, physically crosslinked gels and chemicallycrosslinked adhesives using specifically designed prepolymers of thepresent structure. Structures using the present bioresorbable polymerscan include multilayered structures. Such structures may be incombinations with adhesive layers, hydrophobic or hydrophilic backinglayers, or layers serving other purposes. In addition, the components ofthe various layers may form a composite material at the interface of thelayer including the present bioresorbable polymer and the adhesivelayer.

FIG. 1 depicts a composite bioresorbable patch utilizing the polymers ofthe invention.

The polymers of the present invention may be formed into films or otherstructures and layered or combined with other polymers. For instance, afilm made from the present polymers can be combined with a secondcomponent, where the second component may be, for example, an adhesivepolymer. The polymer/adhesive composition may take a layered structure,and/or may be combined with the other polymer to form a compositestructure. When layers of the present polymer and another polymer areplaced together, they may form a “hybrid composite layer” which denoteshow the two layers interact at the interface, such as by forming ahybrid layer which includes a composite of the present polymer and thesecond component. Alternatively, the combination of the polymer of thepresent invention and, for example, an adhesive polymer could be as ahomogeneous mixture. The second component should include one or manycompounds containing isocyanate reactive functional groups. Isocyanatereactive functional groups may include, but are not limited to amines,hydroxyl groups, thiol groups, and carboxylic acids.

The adhesive polymer can include synthetic polymers and/orpolysaccharides. The synthetic adhesive polymers may includepolyvinyllactam, polyethylene glycol, polyethylene glycol-polypropyleneglycol copolymers, vinyl acetate homo and copolymers, orpoly(vinylalcohol). The polysaccharides may include starch, dextran,agar, cellulose, carboxymethyl cellulose (CMC), hydroxypropyl cellulose(HPC), chitin, chitosan, alginic acid, hyaluronic acid, chondroitinsulfate, heparin, their salts, or mixtures thereof.

The polymers when combined with other polymers may also use acompatibilizing agent. Such compatibilizing agents may include hydrogenbonding materials, such as water, low molecular weight compounds. Lowmolecular weight compounds which may be used as compatibilizing agentsinclude diols, amines, thiols, carboxylic acids. Compatibilizing agentsmay also include PEO and/or PPO containing oligomers, polymers orcopolymers.

Nitrogen containing polymeric compounds may also be included in thesecond component. Such nitrogen containing polymeric compounds mayinclude quaternary ammonium containing copolymers of N-vinyl pyrrolidonethat may or may not contain reactive groups such as aldehydes asdescribed in EP 1 680 546 B1, which is incorporated by reference.

Likewise, one or more hemostatic agents may be included in the secondcomponent. Specific hemostatic agents include oxidized cellulose,gelatin, collagen, and others.

Overall, the strength of the present polymers and/or compositions whichinclude the present polymers can be adjusted to suit the intended use ofthe polymer. The term “strength” or “mechanical strength” describesfavorable mechanical and/or physical characteristics of the presentpolymers and reflects the fact that preferred polymers for use in thepresent invention (generally, as films) having a mechanical strengthwhich is sufficient to allow a suture to be used to anchor the polymerto a tissue site without appreciable tearing or ripping of the film.

Active ingredients or active agents can also be added to the presentbioresorbable polymers. Exemplary bioactive agents which may bedelivered pursuant to the present invention include, for example,anticoagulants, for example heparin and chondroitin sulphate,fibrinolytics such as tPA, plasmin, streptokinase, urokinase andelastase, steroidal and non-steroidal anti-inflammatory agents such ashydrocortisone, dexamethasone, prednisolone, methylprednisolone,promethazine, aspirin, ibuprofen, indomethacin, ketoralac,meclofenamate, tolmetin, calcium channel blockers such as diltiazem,nifedipine, verapamil, antioxidants such as ascorbic acid, carotenes andalpha-tocopherol, allopurinol, trimetazidine, antibiotics, especiallynoxythiolin and other antibiotics to prevent infection, prokineticagents to promote bowel motility, that agents to prevent collagencrosslinking such as cis-hydroxyproline and D-penicillamine, and agentswhich prevent mast cell degranulation such as disodium chromolglycate,among numerous others.

In addition to the above agents, which generally exhibit favorablepharmacological activity related to promoting wound healing, reducinginfection or otherwise reducing the likelihood that an adhesion willoccur, other bioactive agents may be delivered by the polymers of thepresent invention include, for example, amino acids, peptides, proteins,including enzymes, carbohydrates, antibiotics (treat a specificmicrobial infection), anti-cancer agents, neurotransmitters, hormones,immunological agents including antibodies, nucleic acids includingantisense agents, fertility drugs, psychoactive drugs and localanesthetics, among numerous additional agents.

The delivery of these agents will depend upon the pharmacologicalactivity of the agent, the site of activity within the body and thephysicochemical characteristics of the agent to be delivered, and thetherapeutic index of the agent, among other factors. One of ordinaryskill in the art will be able to readily adjust the physicochemicalcharacteristics of the present polymers and thehydrophobicity/hydrophilicity of the agent to be delivered in order toproduce the intended therapeutic effect. The bioactive agents areadministered in concentrations or amounts, which are effective toproduce an intended result. The polymeric composition according to thepresent invention can be used to accommodate a broad range ofhydrophilic and hydrophobic bioactive agents deliver them to sites inthe patient.

Biomedical Applications of the Disclosed Compositions:

The invention is also directed to a bioresorbable patch comprising

-   -   (a) an adhesion barrier component comprising a composition        according to the invention in the form of a film; and    -   (b) n adhesive component comprising:        -   i) at least one synthetic adhesive polymer; and/or        -   ii) at least one polysaccharide.

Preferably, the adhesive polymer is at least one synthetic polymermember selected from the group consisting of, polyvinyllactam,polyethyleneglycol, polyethylene glycol-polypropylene glycol copolymers,vinyl acetate homo and copolymers, and poly(vinyl alcohol) and blendsthereof and the polysaccharide is at least one member selected from thegroup consisting of, starch, dextran, agar, cellulose, carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), chitin, chitosan, alginicacid, hyaluronic acid, chondroitin sulfate, heparin, or their salts andblends thereof

The bioresorbable patch can further comprise at least onecompatibilizing component, which is at least one member selected fromthe group consisting of hydrogen-bonding materials. The hydrogen-bondingmaterial is at least one member selected from the group consisting ofwater, diols, amines, thiols, carboxylic acids, poly(ethyleneoxide (PEO)and/or poly(propyleneoxide (PPO) containing oligomers, polymers andcopolymers.

The bioresorbable patch can further comprise a hybrid composite layer atthe interface between the adhesion barrier and the adhesive layers,wherein the said hybrid composite layer comprises of component (a) andcomponent (b) of the bioresorbable patch. Preferably, component (b)comprises polyvinylpyrrolidone.

The bioresorbable patch can further comprise at least one bioactiveagent.

Adhesion barrier application: A film of the compositions according tothe invention can be employed for use as a barrier film to prevent postsurgical tissue adhesion. The ratio of the hydrophilic polyethyleneoxideunits to the hydrophobic degradable poly hydroxy carboxylic acidsegments in the polymer and the extent of urethane/urea linkages can becontrolled to obtain appropriate degradation profile and strength in thenovel bioresorbable compositions. Solid polymeric compositions ofFormula 1(a)-2(c) of this invention can be used as a bioresorbableadhesion barrier film to prevent post surgical adhesions.

The invention is further directed to a method of wound healing,comprising administering the composition according to the invention orthe bioresorbable patch according to the invention to a patient in needthereof

Preferably, said administration is a partial or total replacement forsutures or staples.

Wound Closure Application:

The composite bioresorbable patch of FIG. 1 can be used as a tissueadhesive patch with an adhesion barrier functionality to preventadhesions in the extra vascular space following surgical procedures. Thebioresorbable patch of this invention is constructed by integration ofan adhesive on to an adhesion barrier. Solid polymeric compositions ofFormula 1(a)-2(c) of this invention can be used as a bioresorbableadhesion barrier component and the adhesive component can be selectedfrom the group containing at least one synthetic adhesive polymer and/orat least one polysaccharide compound. The bioresorbable patch can findparticular use in sutureless closure of caesarean sections after infantdelivery procedures. For surgical closure application, the disclosedbioresorbable adhesive patch construct of FIG. 1 is typically applied asa dry film to the moist tissue surface to support adhesive properties.Following utility of the adhesive component, the patch may be irrigatedwith saline solution or Ringer solution for supporting the adhesionbarrier properties of the patch to prevent undesirable post-surgicaladhesions.

Tissue engineering and wound healing application: The compositionsdisclosed in this invention can be made into porous bioresorbablescaffolds using methods known to those skilled in the art. A specificexample of the porous scaffold that is desired is an open cellinterconnected reticulated structure. The said construct can findutility as a medium to support rapid wound healing via application ofvacuum. The porous constructs from the disclosed compositions along withsupporting media can also be used in a vascular prosthesis device.Supporting media may include biological matrix proteins, or othercomponents to promote endothelialization and tissue regeneration.Vascular prosthesis devices may include vascular access graft, avascular shunt such as an arteriovenous shunt, a replacement for bloodvessel, a bypass vascular prosthesis and other devices known to thoseskilled in the art.

The invention is further related to the use of the composition accordingto the invention as a component in a bioresorbable patch and/or for thetreatment of diseases or conditions related to wound healing, woundclosure, or tissue engineering.

Preferably, the composition according to the invention is used for thetreatment of conditions related to post-surgical adhesions, forsutureless surgical closure, for the manufacture of an implantablemedical device, for the manufacture of a bioresorbable patch, or for thetreatment of diseases or conditions related to wound healing, woundclosure, or tissue engineering.

Testing Procedures used in the following examples of the invention aredescribed below:

Moisture Content:

The moisture content of the starting diol reactant was determined usingthe Karl-Fischer titration method per ASTM E203: Standard Test Methodfor Water Using Volumetric Karl Fischer Titration

Hydroxyl Number and Molecular Weight of Diols:

The hydroxyl number of the diols were determined using ASTM D4274:Standard Test Methods for Testing Polyurethane Raw Materials:Determination of Hydroxyl Numbers of Polyols

Isocyanate Content:

In the polymer and prepolymers was determined by titration using ASTMD2572: Standard Test Methods for Isocyanate Groups in Urethane Materialsor Prepolymers

Molecular Weights of Polymer:

Gel Permeation Chromatography (GPC) for all polymer samples weredetermined using guidelines set in ASTM D5296: Standard Test Method forMolecular Weight Averages and Molecular Weight Distribution ofPolystyrene by High Performance Size-Exclusion Chromatography. GPCweight average molecular weight (Mw) and GPC number average molecularweight (Mn) in Daltons (Da) and the polydispersity index (PI=Mw/Mn) ofthe polyesters (A-B-A′ polymer) were determined by Gel PermeationChromatography (GPC) using polystyrene standards and tetrahydrofuran(THF) as the solvent at 30° C. GPC weight average molecular weight (Mw)and GPC number average molecular weight (Mn) in Daltons (Da) and thepolydispersity index (PI=Mw/Mn) of the polyesterurethanes weredetermined by GPC using polystyrene standards and N,N-dimethylformamide(DMF) as the solvent at 40° C.

Tensile Strength:

Uniaxial tensile strength of polymeric bioresorbable film samples weretested for tensile load at break and elongation at break values on anInstron 5566 instrument at ambient temperature and relative humidityconditions using ASTM D1708: Standard Test Method for Tensile Propertiesof Plastics by Use of Microtensile Specimens.

Synthesis of Materials Example 1 A-B-A′ Polymer with Ratio of EthyleneOxide(EO): Lactide (LLA) of 4.0

Ymer N120 (Structure shown in Formula 4) (pendant MPEG based diol,MW=1090) is dried under N₂ sparging overnight at 105° C. The watercontent as measured using Karl-Fischer technique is <100 ppm. 10.32 g ofthe dried Ymer N120 is loaded into a three neck RBF in a N₂ glove boxalong with 8.44 g of L-lactide (Purac). The reaction vessel is setupwith a N₂ inlet/outlet, a thermocouple thermometer equipped with a datalogger and a glass shaft with Teflon stirrer coupled to a mechanicalstirrer. The reaction vessel is immersed in an oil bath that is heatedstepwise and gradually from room temp to 60° C. and then to 125° C. At60° C., about 10 g of anhydrous diethyleneglycol dimethyl ether is addedto the reaction mixture to bring it into a clear-colorless solution.Stannous octoate 0.051 g is added to the reaction mixture and thereaction temperature is ramped up to 125-130° C. The reaction mixture isheld at this temperature for 3 hours at end of which the heating isstopped and the reaction mixture cooled to 70-75° C.

Polyesterurethane (PEsU)—Chain Extended A-B-A′ Polymer with Ratio ofEthylene Oxide(EO): Lactide (LLA) of 4.0

About 70 g anhydrous 1, 4-dioxane is added to the above reaction mix at70-75° C. with continuous stirring. To the resultant clear solution,1.43 g of 1,6-hexamethylene diisocyanate (HDI) is added and the reactionis allowed to continue for ˜6 hours until the —NCO value reached thetheoretical expected number (as measured by ASTM D2572-97 Standard TestMethods for Isocyanate Groups in Urethane Materials or Prepolymers). Atthe end of the reaction a viscous mass resulted and the heat is cut offallowing the reaction mixture to cool to room temperature. Additionalanhydrous 1,4 dioxane is added to reduce the viscosity and the polymercrashed into isopropyl alcohol. In this case, a viscous polymer solutionseparated out and settled to the bottom of the extraction vessel. Thesupernatant liquid is decanted and the polymer solution is dried firstat room temperature under vacuum for 24-36 h and then the temperature isslowly raised to 40° C. and the drying continued for additional 72 hunder vacuum. At the end of the drying operation, the oven is cooled toroom temperature and the vacuum broken with N₂. The resultant polymer isa viscous liquid of MW of 54,253 daltons (Mn) that flows very slowly atroom temperature, and has the formula shown in Formula 5.

Example 2 A-B-A′ Polymer with Ratio of Ethylene Oxide(EO): Lactide (LLA)of 2.0

Ymer N120 [Structure shown in Formula 4] (pendant MPEG based diol,MW=1090) is dried under N₂ sparging overnight at 105° C. The watercontent as measured using Karl-Fischer technique is <100 ppm. 7.45 g ofthe dried Ymer N120 is loaded into a three neck RBF in a N₂ glove boxalong with 12.19 g of L-lactide (Purac). The reaction vessel is setupwith a N₂ inlet/outlet, a thermocouple thermometer equipped with a datalogger and a glass shaft with Teflon stirrer coupled to a mechanicalstirrer. The reaction vessel is immersed in an oil bath that ias heatedstepwise and gradually from room temp to 60° C. and then to 125° C. At60° C., about 10 g of anhydrous diethyleneglycol dimethyl ether is addedto the reaction mixture to bring it into a clear-colorless solution.Stannous octoate 0.073 g is added to the reaction mixture and thereaction temperature is ramped up to 125-130° C. The reaction mixture isheld at this temperature for 3 hours at end of which the heating isstopped and the reaction mixture cooled to 70-75° C.

Polyesterurethane (PEsU)—Chain Extended A-B-A′ Polymer with Ratio ofEthylene Oxide(EO): Lactide (LLA) of 2.0

About 70 g anhydrous 1, 4-dioxane is added to the above reaction mix at70-75° C. with continuous stirring. To the resultant clear solution,1.04 g of 1,6-hexamethylene diisocyanate (HDI) is added and the reactionis allowed to continue for ˜6 hours until the —NCO value reached thetheoretical expected number (as measured by ASTM D2572 Standard TestMethods for Isocyanate Groups in Urethane Materials or Prepolymers). Atthe end of the reaction a viscous mass resulted and the heat is cut offallowing the reaction mixture to cool to room temperature. Additionalanhydrous 1,4 dioxane is added to reduce the viscosity and the polymercrashed into isopropyl alcohol yielding a white precipitate. Theprecipitate is filtered and under dried vacuum for 24 h and then thetemperature is slowly raised to 40 C and the drying continued foradditional 72 h under vacuum. At the end of the drying operation, theoven is cooled to room temperature and the vacuum broken with N₂. Theresultant polymer is in the form of white flakes, of MW of 61,429daltons (Mn) and has the following formula shown in Formula 5.

Example 3 A-B-A′ Polymer with Ratio of Ethylene Oxide(EO): Lactide (LLA)of 0.5

Ymer N120 [Structure shown in Formula 4] (pendant MPEG based diol,MW=1090) is dried under N₂ sparging overnight at 105° C. The watercontent as measured using Karl-Fischer technique is <100 ppm. 2.60 g ofthe dried Ymer N120 is loaded into a three neck RBF in a N₂ glove boxalong with 16.99 g of L-lactide (Purac). The reaction vessel is setupwith a N₂ inlet/outlet, a thermocouple thermometer equipped with a datalogger and a glass shaft with Teflon stirrer coupled to a mechanicalstirrer. The reaction vessel is immersed in an oil bath that ias heatedstepwise and gradually from room temp to 60° C. and then to 125° C. At60° C., about 10 g of anhydrous diethyleneglycol dimethyl ether is addedto the reaction mixture to bring it into a clear-colorless solution.Stannous octoate 0.102 g is added to the reaction mixture and thereaction temperature is ramped up to 125-130° C. The reaction mixture isheld at this temperature for 3 hours at end of which the heating isstopped and the reaction mixture cooled to 70-75° C.

Polyesterurethane (PEsU)—Chain Extended A-B-A′ Polymer with Ratio ofEthylene Oxide(EO): Lactide (LLA) of 0.5

About 70 g anhydrous 1, 4-dioxane is added to the above reaction mix at70-75° C. with continuous stirring. To the resultant clear solution,0.41 g of 1,6-hexamethylene diisocyanate (HDI) is added and the reactionis allowed to continue for ˜6 hours until the —NCO value reached thetheoretical expected number (as measured by ASTM D2572 Standard TestMethods for Isocyanate Groups in Urethane Materials or Prepolymers). Atthe end of the reaction a viscous mass resulted and the heat is cut offallowing the reaction mixture to cool to room temperature. Additionalanhydrous 1,4 dioxane is added to reduce the viscosity and the polymercrashed into isopropyl alcohol yielding a white precipitate. Theprecipitate is filtered and under dried vacuum for 24 h and then thetemperature is slowly raised to 40 C and the drying continued foradditional 72 h under vacuum. At the end of the drying operation, theoven is cooled to room temperature and the vacuum broken with N₂. Theresultant polymer is in the form of white flakes, of MW of 203,445daltons (Mn) and has the following formula shown in Formula 5.

Example 4 Film Formation and Testing Data

10 g of the synthesized polymer from Example 1,2 or 3 are dissolved indichloromethane to yield 40 g of viscous solution (25 wt % solids). Thesolution is cast into a film on silicone coated Mylar using a Gardnerblade coater to yield 10 mil films after drying in an inert atmosphereof N₂. Dog bones are cut from the dried film and used for tensiletesting to determine the Tensile load at break and Elongation at breakvalues according to ASTM D1708. The number average molecular weights ofthe polymers are determined using GPC according to ASTM D5296.

The physical properties of the A-B-A′ polymers and Polyesterurethane(PEsU) polymers are summarized in Table 1.

TABLE 1 Physical properties of the A-B-A′ polymers and Polyesterurethanepolymers Polyester PEsU Tensile EO/LLA GPC Mn, GPC Mn, Load atElongation Ratio Da (PI) Da (PI) break, N at break, % 0.5 11,875 203,44518.06 208 (Ex. 4.1) (1.38) (1.90) 2.0 5,554 61,429 0.03 42 (Ex. 4.2)(1.09) (1.66) 4.0 3,411 54,253 Highly Viscous Liquid (Ex. 4.3) (1.19)(1.71)

Solid polymers of this invention, such as Examples 4.1 and 4.2 in Table1 above, are suitable candidates for use as a barrier film component forconstruction of a bioresorbable patch.

Example 5 Procedure for Construction of a Bioresorbable Adhesive PatchDevice

A bioresorbable patch of the invention can be prepared by a method asshown in the following scheme 1:

According to the method set forth in scheme 1, a base substance iscoated with a bioresorbable polymer of the invention (such as a 20%solution) in combination with a solvent (such as DCM). The obtainedcoated substance is dried, and the dried product is coated with asolution of the desired adhesive (such as 20% solution of PVP), and thendried. The dried product is then separated/peeled off of the basesubstrate to provide the final product patch.

The adhesion barrier polymer (Component 1) was first dissolved indichloromethane (DCM) to make a 20 wt % solution which was cast into athin film (5-10 mil thickness), using a Gardner blade coater, on a basefilm substrate and dried completely under inert atmosphere. The basesubstrate chosen in the patch construction was commercially availablesilicone coated polyester (Mylar) film. The adhesive (Component 2) wasalso made into a 20 wt % solution in DCM and coated on the above driedbarrier film followed by drying at room temperature. The resultingbioresorbable adhesive patch was easily peeled off from the basesubstrate for use in closure applications. The bioresorbable adhesivepatch construct was robust and did not delaminate upon storage. Due tothe solubility of both the adhesion barrier and the adhesive componentin DCM, an integrated patch is formed as a result of a composite layer,linking the two functional components of the bioresorbable patch. Thebioresorbable patch structure can be visualized as a three layeredconstruct (see Scheme 1) wherein the adhesion barrier and the adhesiveis integrated through the hybrid composite interfacial layer.Additionally the formation of the composite interfacial layer isenhanced due to the compatibilizing effect of polyethyleneoxide presentin the barrier to the adhesive polyvinylpyrrolidone layer.

The invention being thus described generically and with reference tospecific embodiments, it will be readily apparent to those skilled inthe art that the same may be varied in many ways.

1. A bioresorbable patch comprising: (a) an adhesion barrier componentcomprising, in the form of a patch, a composition comprising at leastone polymer having the structure A-B-A′, wherein A and A′ may be thesame or different and each is a degradable polyester component andwherein B is the reaction product resulting from the reaction between Aand A′ and a diol having one or more pendant oligomeric or polymericgroups; and (b) an adhesive component comprising: (i) at least onesynthetic adhesive polymer; and/or (ii) at least one polysaccharide. 2.The bioresorbable patch of claim 1, wherein said adhesive polymer is atleast one synthetic polymer member selected from the group consistingof, polyvinyllactam, polyethyleneglycol, polyethyleneglycol-polypropylene glycol copolymers, vinyl acetate homo andcopolymers, and poly(vinyl alcohol) and blends thereof.
 3. Thebioresorbable patch of claim 1, wherein said polysaccharide is at leastone member selected from the group consisting of, starch, dextran, agar,cellulose, carboxymethyl cellulose (CMC), hydroxypropylcellulose (HPC),chitin, chitosan, alginic acid, hyaluronic acid, chondroitin sulfate,heparin, or their salts and blends thereof.
 4. The bioresorbable patchof claim 1, further comprising at least one compatibilizing component.5. The bioresorbable patch of claim 2, wherein said compatibilizingcomponent is at least one member selected from the group consisting ofhydrogen-bonding materials.
 6. The bioresorbable patch of claim 5,wherein said hydrogen-bonding material is at least one member selectedfrom the group consisting of water, diols, amines, thiols, carboxylicacids, poly(ethyleneoxide (PEO) and/or poly(propyleneoxide (PPO)containing oligomers, polymers and copolymers.
 7. The bioresorbablepatch of claim 1, further comprising a hybrid composite layer at theinterface between the adhesion barrier and the adhesive layers, whereinthe said hybrid composite layer comprises of component (a) and component(b).
 8. The bioresorbable patch of claim 7, wherein component (II)comprises polyvinylpyrrolidone.
 9. The bioresorbable patch of claim 1,further comprising at least one bioactive agent.
 10. A method of woundhealing comprising applying the bioresorbable patch of claim 1 to apatient in need thereof.
 11. The method of claim 10, wherein applicationof said bioresorbable patch is a partial or total replacement forsutures or staples.